The present invention is concerned with novel thiazole derivatives that inhibit binding of adhesive proteins to the surface of cells by influencing cell-cell and cell-matrix interactions.
The subject invention provides compounds having the formula: 
wherein
R1 is 
R2 is 
R3 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, carboxy, alkyl-Oxe2x80x94COxe2x80x94, or aralkyl-Oxe2x80x94COxe2x80x94;
R4 is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl;
R5 and R6 are each independently hydrogen, alkyl, cycloalkyl, or heteroaryl;
R7 and R8 are each independently hydrogen, alkyl, cycloalkyl, or aralkyl, or R7 and R8 together with the N atoms to which they are attached form a 5- to 8-membered heterocyclic ring that is either unsubstituted or substituted with alkyl;
R9 is hydrogen, alkyl, or cycloalkyl;
R10 is aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydrogen, or alkyl, or R10 is carboxy, carboxyalkyl, alkyl-Oxe2x80x94COxe2x80x94, aralkyl-Oxe2x80x94COxe2x80x94, alkyl-COxe2x80x94, aralkyl-COxe2x80x94, heteroarylalkyl-COxe2x80x94, alkylsulphonyl, arylsulphonyl or heteroarylsulphonyl and k is zero, or R10 is an xcex1-amino acid bonded via the amino group and l is zero and k is 1;
A is carbonyl or sulphonyl;
B is hydrogen, alkyl, or cycloalkyl;
a is an integer from 0 to 2 but not being zero when R1 is xe2x80x94NH2; b is an integer from 0 to 4; c, d, f, g, k, l and m are each independently an integer from 0 to 1, whereby c, f and g
are not simultaneously 0 and whereby m is not 0 when f or g is 1; i is an integer from 0 to 1, whereby k and l are also 0 when i is 0; e is an integer from 0 to 3; h is an integer from 0 to 5; j is an integer from 0 to 2; and the sum of e, h and j is an integer from 2 to 7;
and the pharmaceutically usable salts and esters thereof. Although recited as a single grouping, all combinations of the mentioned substituents are envisioned.
It is preferred that f and g are not both 1. It is also preferred where R2 is 
and R9, R10, A, B, c and f to l are as defined above, or 
and R10, A, B and f to l are as defined above, or 
and R9, R10, A, d, e and h to l are as defined in claim 1, or 
and R9, R10, c, e, g and h to l are as defined above, and c and g cannot simultaneously equal 0.
It is favored when arylene is phenylene or phenylene that is substituted with one or more substituents selected from the group consisting of alkoxy, aralkoxy, halogen, and alkoxy-alkoxy. Especially favored is where arylene is meta- or para-phenylene or substituted meta- or para-phenylene, with the substituents of the phenylene previously given by the definition of R2 standing meta- or para- to one another and with the substituted phenylene carrying an additional substituent on the ring selected from the group of alkoxy, alkoxy-alkoxy, halogen or aralkoxy.
R3 is preferably hydrogen, alkyl, cycloalkyl, alkyl-Oxe2x80x94COxe2x80x94, carboxy or unsubstituted or substituted phenyl, with the substituted phenyl being substituted by one or more substituents selected from halogen, nitro and amino. R4 is preferably hydrogen, alkyl, cycloalkyl, phenyl, or pyridyl. R5 and R6 are preferably hydrogen or pyridyl and R7 and R8 are hydrogen, or R5 and R6 are each hydrogen or pyridyl and R7 and R8 together with the N atoms to which they are attached form a 5- or 6-membered ring. R10 is preferably piperidyl, pyridylmethyl, pyridyl, benzyl, alkyl, hydrogen or substituted or unsubstituted phenyl, with the substituted phenyl being mono- or multiply-substituted by halogen, alkoxy, alkoxycarbonyl, carboxy or hydroxy, or R10 is alkyl-Oxe2x80x94CO-methyl, carboxymethyl, alkylsulphonyl, alkyl-COxe2x80x94, benzyl-Oxe2x80x94COxe2x80x94 or alkyl-Oxe2x80x94COxe2x80x94, with k being equal to zero, or R10 is L-valine, L-phenylalanine, L-phenylglycine, L-leucine, L-isoleucine, L-serine, L-threonine, 3-(1-naphthyl)-L-alanine, 3-(2-naphthyl)-L-alanine, N-isopropyl-glycine, xcex2-cyclohexyl-L-alanine or L-proline, with k being equal to 1 and l being equal to zero.
Other preferred compounds include where R9 is hydrogen or cycloalkyl and where R2 is bonded to position 5 of the thiazole ring and R3 is bonded to position 4 of the thiazole ring.
A favored subgenus is where compound of formula I is a compound having the formula: 
wherein R1xe2x80x2 is 
R2xe2x80x2 is 
A is carbonyl or sulphonyl;
c, d, f, g, k, l and m are each independently an integer from 0 to 1, whereby c, f and g are not simultaneously 0 and whereby m is not 0 when f or g is 1; i is an integer from 0 to 1, whereby k and l are also 0 when i is 0; e is an integer from 0 to 3; h is an integer from 0 to 5; j is an integer from 0 to 2; and the sum of e, h and j is an integer from 2 to 7; and
R10xe2x80x2 is phenyl; phenyl substituted with halogen, hydroxy, or alkoxy; carboxy; carboxy alkyl, alkyl, or pyridine;
R3xe2x80x2 is hydrogen or alkyl.
A preferred group of compounds is where R1xe2x80x2 is 
and R3xe2x80x2 is alkyl, e.g. methyl or tert-butyl, A is carbonyl, and R10xe2x80x2 is phenyl, phenyl substituted with chlorine, phenyl substituted with methoxy, or pyridine.
An alternative preferred group of compounds is where A is sulphonyl.
Another preferred group of compounds is where R1xe2x80x2 is 
In such a group, it is preferred that R1xe2x80x2 is hydrogen and R10xe2x80x2 is phenyl, alkyl, or pyridine.
The subject invention provides a process for manufacturing compounds of formula I (as used for the remainder of the Summary of the Invention, the phrase xe2x80x9cthe compounds of formula Ixe2x80x9d also includes the pharmaceutically usable salts and esters of the formula I) which comprises reacting a compound of the formula: 
with an amine of the formula: 
wherein R1, R3, R9, R10, A, B and d to m are as above, c is equal to 1 and R03 is alkyl or aralkyl.
Novel intermediates in this process include compounds of the formula: 
wherein R1 is 
R3 is alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, carboxy, alkyl-Oxe2x80x94COxe2x80x94, or aralkyl-Oxe2x80x94COxe2x80x94, wherein R3 is not hydrogen or methyl when R1 is 
a is an integer from 0 to 2 but not being 0 when R1 is xe2x80x94NH2.
Pharmaceutical compositions provided by the subject invention include an effective amount of a compound of formula I and a pharmaceutically acceptable carrier.
The subject invention further provides a method for treating or preventing illnesses which are caused by a malfunction of the binding of adhesive proteins to vitronectin receptors, which comprises administering to a subject in need of such treating or preventing an effective amount of a compound of formula I.
The invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting the invention.
The invention is concerned especially with thiazole derivatives of formula I 
wherein
R1 is 
R2 is 
R3 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, carboxy, alkyl-Oxe2x80x94COxe2x80x94 or aralkyl-Oxe2x80x94COxe2x80x94;
R4 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
R5and R6 are each independently hydrogen, alkyl, cycloalkyl or heteroaryl;
R7 and R8 are each independently hydrogen, alkyl, cycloalkyl or aralkyl or R7 and R8 together with the N atoms to which they are attached form a 5- to 8-membered heterocyclic ring which can be alkyl-substituted;
R9 is hydrogen, alkyl or cycloalkyl;
R10 is aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydrogen or alkyl, or R10 is carboxy, carboxyalkyl, alkyl-Oxe2x80x94COxe2x80x94, aralkyl-Oxe2x80x94COxe2x80x94, alkyl-COxe2x80x94, aralkyl-COxe2x80x94, heteroarylalkyl-COxe2x80x94, alkylsulphonyl, arylsulphonyl or heteroarylsulphonyl and k is zero, or R10 is an xcex1-amino acid bonded via the amino group and l is zero and k is 1;
A is carbonyl or sulphonyl;
B is hydrogen, alkyl or cycloalkyl;
a to m are zero or whole positive numbers, with a being zero to 2 but not being zero when R1 is xe2x80x94NH2; b being zero to 4; c, d, f, g, k, l and m each independently being zero or 1, whereby c, f and g are not simultaneously zero and whereby m is not zero when f or g is 1; i is zero or 1, whereby k and l are also zero when i is zero; e is zero to 3; h is zero to 5; j is zero to 2; and the sum of e, h and j is 2 to 7;
and their pharmaceutically usable salts and esters.
The compounds of formula I and their pharmaceutically usable salts and esters are novel and have valuable pharmacological properties. In particular, they inhibit the binding of adhesive proteins such as fibrinogen, vitronectin, von Willebrand factor, fibronectin, thrombospondin and osteopontin to the vitronectin receptors (such as e.g. xcex1vxcex23, xcex1vxcex25, xcex1vxcex26, xcex1vxcex28, etc.) on the surface of various types of cell. The compounds therefore influence cell-cell and cell-matrix interactions and can be used in the treatment and prophylaxis of illnesses caused by a malfunction of the binding of adhesive proteins to vitronectin receptors. In particular, they can be used as vitronectin receptor antagonists in the prophylaxis or treatment of neoplasms, tumor metastasis, tumor growth, osteoporosis, Paget""s disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure as well as infections caused by viruses, bacteria or fungi.
Objects of the present invention are the compounds of formula I and their aforementioned salts and esters per se and their use as therapeutically active substances, a process for the manufacture of the compounds, intermediates, pharmaceutical compositions, medicaments containing the compounds, their salts or esters, the use of the compounds, solvates and salts for the prophylaxis and/or therapy of illnesses, especially in the treatment or prophylaxis of, for example, neoplasms, tumor metastasing, tumor growth, osteoporosis, Paget""s disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure as well as infections caused by viruses, bacteria or fungi, and the use of the compounds and salts for the production of medicaments for the treatment or prophylaxis of, for example, neoplasms, tumor metastasing, tumor growth, osteoporosis, Paget""s disease, diabetic retinopathy, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure as well as infections caused by viruses, bacteria or fungi.
In the present description the term xe2x80x9calkylxe2x80x9d, alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, preferably a straight or branched-chain alkyl group with 1-4 carbon atoms. Examples of straight-chain and branched C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, preferably methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and pentyl.
The term xe2x80x9ccycloalkylxe2x80x9d, alone or in combination, signifies a cycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to 6 carbon atoms. Examples of C3-C8 cycloalkyl are cyclopropyl, methyl-cyclopropyl, dimethylcyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, methyl-cyclohexyl, dimethyl-cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl and particularly cyclopentyl.
The term xe2x80x9calkoxyxe2x80x9d, alone or in combination, signifies a group of the formula alkyl-Oxe2x80x94 in which the term xe2x80x9calkylxe2x80x9d has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secbutoxy and tert.butoxy, preferably methoxy and ethoxy.
The term xe2x80x9calkoxy-alkoxyxe2x80x9d, alone or in combination, signifies an alkoxy group as previously defined in which one hydrogen atom has been replaced by an alkoxy group. Examples of alkoxy-alkoxy are methoxy-methoxy and methoxy-ethoxy, preferably 2-methoxy-ethoxy.
The term xe2x80x9carylxe2x80x9d, alone or in combination, signifies a phenyl or naphthyl group which optionally carries one or more substituents each independently selected from alkyl, alkoxy, halogen, carboxy, alkoxycarbonyl, aminocarbonyl, hydroxy, amino, nitro and the like, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-tert.butoxyphenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 1-naphthyl and 2-naphthyl. Preferred are phenyl, alkoxy-phenyls, 2-hydroxy-3,5-dichlorophenyl, chlorophenyls, nitrophenyls and aminophenyls, especially phenyl and ortho-, meta- and para-mono-chlorophenyls, particularly para- and meta-chlorophenyl, and para- and meta-methoxy-phenyl.
The term xe2x80x9caryloxyxe2x80x9d, alone or in combination, signifies a group of the formula aryl-Oxe2x80x94 in which the term xe2x80x9carylxe2x80x9d has the previously given significance. Phenyloxy is an example of such an aryloxy group.
The term xe2x80x9caralkylxe2x80x9d, alone or in combination, signifies an alkyl or cycloalkyl group as previously defined in which one hydrogen atom has been replaced by an aryl group as previously defined, such as benzyl, 2-phenylethyl and the like, preferably benzyl.
The term xe2x80x9caralkoxyxe2x80x9d, alone or in combination, signifies an alkoxy group as previously defined in which one hydrogen atom has been replaced by an aryl group as previously defined. Benzyloxy is a preferred example of an aralkoxy group.
The term xe2x80x9carylenexe2x80x9d, alone or in combination, signifies a phenylene or naphthylene group which optionally carries one or more substituents selected from alkyl, cycloalkyl, alkoxy, halogen, hydroxy, amino, nitro, aryloxy, aralkoxy and alkoxy-alkoxy, preferably alkoxy, benzyloxy, chloro and alkoxy-alkoxy. Examples are ortho-, meta- or para-phenylenes, the tolylenes, the methoxyphenylenes, the tert-butoxyphenylenes, the fluorophenylenes, the chlorophenylenes, the hydroxyphenylenes, the naphthylenes, the benzyloxyphenylenes etc. Preferred are meta- and parphenylenes, with the substituents of the phenylene previously given by the definition of R2 standing meta- or para- to each other and with additionally one or more substituents selected from alkyl, cycloalkyl, alkoxy, halogen, hydroxy, amino, aryloxy and alkoxy-alkoxy optionally being present on the arylene ring. Especially preferred are meta- and para- phenylene which additionally carry a substituent selected from alkoxy, benzyloxy, chloro and alkoxy-alkoxy, particularly methoxy-phenylene, benzyloxyphenylene and 2-methoxy-ethoxy-phenylene. Quite particularly preferred are meta- and para- phenylene.
The term xe2x80x9cheterocyclylxe2x80x9d, alone or in combination, signifies a saturated, partially unsaturated or aromatic 5- to 10-membered heterocycle which contains one or more hetero atoms selected from nitrogen, oxygen and sulphur. If desired, it can be substituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo etc. and/or on a secondary nitrogen atom (i.e. xe2x80x94NHxe2x80x94) by alkyl, cycloalkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiary nitrogen atom (i.e.=Nxe2x80x94) by oxido, with halogen, alkyl, cycloalkyl and alkoxy being preferred. Examples of such heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazoyl, imidazoyl (e.g. imidazol-4-yl and 1-benzyloxycarbonyl-imidazol-4-yl), pyrazoyl, pyridyl, pyrazinyl, pyrimidinyl, hexahydro-pyrimidinyl, furyl, thienyl, thiazolyl, oxazolyl, indolyl (e.g. 2-indolyl), quinolyl (e.g. 2-quinolyl, 3-quinolyl and 1-oxido-2-quinolyl), isoquinolyl (e.g. 1-isoquinolyl and 3-isoquinolyl), tetrahydroquinolyl (e.g. 1,2,3,4-tetrahydro-2-quinolyl), 1,2,3,4-tetrahydroisoquinolyl (e.g. 1,2,3,4-tetrahydro-1-oxo-isoquinolyl) and quinoxalinyl. Preferred are 5- or 6-membered rings, especially piperidyl and pyridyl.
The term xe2x80x9cheteroarylxe2x80x9d, alone or in combination, signifies the aromatic compounds which fall under the definition of xe2x80x9cheterocyclylxe2x80x9d and which can carry the substituents described there. Preferred are 5- and 6-membered rings, especially pyridyl.
The term xe2x80x9caminoxe2x80x9d, alone or in combination, signifies a primary, secondary or tertiary amino group bonded via the nitrogen atom, with the secondary amino group carrying an alkyl or cycloalkyl substituent and the tertiary amino group carrying two similar or different alkyl or cycoalkyl substituents or the two nitrogen substitutents together forming a ring, such as, for example, xe2x80x94NH2, methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl or piperidino etc., preferably amino, dimethylamino and diethylamino and particularly primary amino.
The term xe2x80x9chalogenxe2x80x9d signifies fluorine, chlorine, bromine or iodine and preferably chlorine or bromine, and particularly chlorine.
As examples of xe2x80x9cxcex1-amino acidsxe2x80x9d bonded via the amino group there come into consideration xcex1-amino acids having the L- or D-configuration in which the carboxyl group present is optionally derivatized as an ester or amide. Examples of such xcex1-amino acids are L-valine, L-phenylalanine, L-leucine, L-isoleucine, L-serine, L-threonine, 3-(1-naphthyl)-L-alanine, 3-(2-naphthyl)-L-alanine, N-isopropyl-glycine, xcex2-cyclohexyl-L-alanine, L-phenylglycine and L-proline. Preferred are alanine, valine, phenylanine, leucine, xcex2-cyclohexyl-alanine and phenylglycine, especially phenylglycine and valine.
The term xe2x80x9ccarboxyxe2x80x9d, alone or in combination, signifies a xe2x80x94COOH group.
The term xe2x80x9ccarboxyalkylxe2x80x9d alone or in combination, signifies an alkyl group as previously described in which one hydrogen atom has been replaced by a carboxy group. The carboxymethyl group is preferred.
The term xe2x80x9calkyl-Oxe2x80x94COxe2x80x94xe2x80x9d, alone or in combination, signifies an alkyl ester group, with alkyl being as previously defined. The methyl ester, ethyl ester, isomeric propyl ester and isomeric butyl ester groups are preferred. The methyl ester, ethyl ester and tert.butyl ester groups are especially preferred.
The term xe2x80x9calkyl-COxe2x80x94xe2x80x9d, alone or in combination, signifies an alkylcarbonyl group, with alkyl being as previously defined. Examples are methylcarbonyl, ethylcarbonyl and the isomeric propylcarbonyls and butylcarbonyls. Ethylcarbonyl is particularly preferred.
The term xe2x80x9caralkyl-Oxe2x80x94COxe2x80x94xe2x80x9d, alone or in combination, signifies an aralkyl ester group, with aralkyl being as previously defined. The benzyl ester group is especially preferred.
The term xe2x80x9cheterocyclylalkylxe2x80x9d, alone or in combination, signifies an alkyl group as previously defined in which one hydrogen atom has been replaced by a heterocyclyl group. Examples of such heterocyclylalkyls are pyridylmethyl and piperidylmethyl.
The term xe2x80x9cheteroarylalkylxe2x80x9d, alone or in combination, signifies an alkyl group as previously defined in which one hydrogen atom has been replaced by a heteroaryl group. Preferred are, for example, 2-pyridylmethyl and 3-pyridylmethyl.
The term xe2x80x9calkylsulphonylxe2x80x9d, alone or in combination, signifies a 
group in which Alkyl is as previously defined. Preferred alkylsulphonyls are methylsulphonyl, ethylsulphonyl and especially propylsulphonyl.
The term xe2x80x9carylsulphonylxe2x80x9d, alone or in combination, signifies a 
group in which Aryl is as previously defined. Preferred arylsulphonyls are phenylsulphonyl, 1-naphthylsulphonyl, p-toluenesulphonyl and 2-naphthylsulphonyl.
The term xe2x80x9cheteroarylsulphonylxe2x80x9d, alone or in combination, signifies a 
group in which heteroaryl is as previously defined. Preferred heteroarylsulphonyls are 2-thiophenesulphonyl and 3,5-dimethylisoxazol-4-sulphonyl.
Examples of physiologically usable salts of the compounds of formula I are salts with physiologically compatible mineral acids such hydrochloric acid, sulphuric acid or phosphoric acid; or with organic acids such as methanesulphonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The compounds of formula I with free carboxy groups can also form salts with physiologically compatible bases. Examples of such salts are alkali metal, alkali earth metal, ammonium and alkylammonium salts such as the Na, K, Ca or tertramethylammonium salt. The compound of formula I can also be present in the form of zwitterions.
In the nomenclature used in the present description the ring atoms of the thiazole ring are numbered as follows: 
in which substituent R1 is bonded to position 2, substituent R2 is bonded to position 4 and R3 is bonded to position 5: 
or substituent R2 is bonded to position 5 and substituent R3 is bonded to position 4 of the thiazole ring: 
The invention expressly includes pharmaceutically suitable derivatives of the compounds of formula I. For example, the COOH groups in R2 can be esterified. The alkyl and aralkyl esters are examples of suitable esters. The methyl, ethyl, propyl, butyl, benzyl and (R/S)-1-((isopropoxy-carbonyl)-oxy)-ethyl esters are preferred esters. The methyl, ethyl and tert.butyl esters are especially preferred.
The compounds of formula I can also be solvated, e.g. hydrated. The solvation can be effected in the course of the manufacturing process or can take place e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration).
The compounds of formula I can contain several asymmetric centres and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
A preferred embodiment of the invention comprises compounds of formula I in which f and g are not both simultaneously 1.
A further preferred embodiment comprises compounds of formula I in which f and g are not the same.
Preferred compounds of formula I are also those in which R2 is 
especially those in which R2 is 
Also preferred are compounds of formula I in which R2 is 
Likewise preferred compounds of formula I are those in which R2 is 
Preferred compounds are compounds of formula I in which R2 is bonded to position 5 and R3 is bonded to position 4 of the thiazole ring. Especially preferred compounds of formula I are those in which R2 is defined in accordance with formula III, IVa, IVb or V and is bonded to position 5 of the thiazole ring with R3 being bonded to position 4 of the thiazole ring.
Likewise preferred compounds of formula I are those in which R2 is 
and wherein in compounds of formula VIb g is equal to 1 when c stands for zero.
Also preferred are compounds of formula I in which R2 is 
and in which g is equal to 1 when c is equal to zero.
Likewise preferred are compounds of formula I in which R2is 
The compounds of formula I in which R2 is equal to formula VId, A is equal to carbonyl and R2 is bonded to position 4 of the thiazole ring are especially preferred. The compounds in which R2 is equal to formula VId, A is equal to carbonyl, e is equal to 1 and R2 is bonded to position 4 of the thiazole ring are particularly preferred.
Also preferred is the embodiment of the invention in which in formula I f and g are both 1, R2 corresponds to formula V, A is carbonyl and B is hydrogen.
Furthermore, the compounds of formula I in which c is 1, d is zero, f and g are both zero and A is equal to carbonyl are preferred.
Likewise preferred are the compounds of formula I in which c is 1, d is 1 and f, g and m are zero.
Preferred compounds of the above-described are compounds in which arylene is a phenylene or substituted phenylene in which the phenylene can be mono- or multiply substituted with alkoxy, alkoxy-alkoxy, halogen, aralkoxy, especially benzyloxy. Especially preferred are compounds in which arylene is meta- or para-phenylene or substituted meta- or para-phenylene in which the substituents of the phenylene previously given by the definitions of R2 stand meta- or para- to one another and in which the substituted phenylene carries on the ring one or more additional substituents selected from the group of alkoxy, alkoxy-alkoxy, halogen or aralkoxy, especially benzyloxy.
Especially preferred are compounds in which arylene is meta- or para-phenylene or substituted meta- or para-phenylene in which the substituents of the phenylene previously given by the definitions of R2 stand meta- or para- to one another and in which the substituted phenylene carries on the ring an additional substitutent selected from the group of alkoxy, alkoxy-alkoxyhalogen or aralkoxy, especially benzyloxy. Especially preferred substituents on the phenylene are methoxy, 2-methoxy-ethoxy, chlorine and benzyloxy.
Compounds of formula I in which arylene is meta- or para-phenylene are especially preferred.
To the preferred compounds described above there belong those in which R1 is 
Especially preferred are compounds of formula I in which R1 is 
Also preferred are compounds of formula I in which R3 is hydrogen, alkyl, cycloalkyl, carboxy, alkyl-Oxe2x80x94COxe2x80x94 or substituted or unsubstituted phenyl, with the substituted phenyl being substituted by one or more substituents, preferably one substituent, selected from the group of halogen, nitro and amino, preferably nitro and/or amino. Particularly preferred significances of R3 are the following: hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, cyclopentyl, methyl-Oxe2x80x94COxe2x80x94, carboxy, phenyl, nitrophenyl and aminophenyl.
A group of preferred compounds of formula I comprises those in which R4 is hydrogen, alkyl, cycloalkyl, phenyl or pyridyl. Especially preferred are compounds of formula I in which R4 is hydrogen, alkyl, phenyl or pyridin-2-yl.
To the group of preferred compounds of formula I also belong those in which R5 and R6 are hydrogen or pyridyl, preferably hydrogen, and R7 and R8 are hydrogen or R5 and R6 are each hydrogen or pyridyl, preferably hydrogen, and R7 and R8 together with the N atoms to which they are attached form a 5- or 6-membered ring, especially an imidazolidine or hexahydropyrimidine ring. Especially preferred are the compounds of formula I in which R7 and R8 together with the N atoms to which they are attached form an imidazolidine ring. Particularly preferred are those compounds of formula I in which R5, R6, R7 and R8 are hydrogen.
Also preferred is the group of compounds of formula I which R9 is hydrogen or cycloalkyl. The compounds in which R9 is hydrogen or cyclopropyl are especially preferred. Of these the compounds, in which R9 is hydrogen are particularly preferred.
Preferred compounds of formula I are those in which R10 is piperidyl, pyridyl-methyl, pyridyl, benzyl, alkyl, hydrogen or substituted or unsubstituted phenyl, with the substituted phenyl being mono- or multiply-substituted by halogen, alkoxy, alkoxycarbonyl, carboxy or hydroxy, or R10 is alkyl-Oxe2x80x94CO-methyl, carboxymethyl, alkylsulphonyl, alkyl-COxe2x80x94, benzyl-Oxe2x80x94COxe2x80x94 or alkyl-Oxe2x80x94COxe2x80x94, whereby here k is zero.
Furthermore, preferred compounds of formula I are those in which R10 is an xcex1-amino acid bonded via the amino group, with l being zero and k being 1, especially in which R10 is L-valine, L-phenylalanine, L-phenylglycine, L-leucine, L-isoleucine, L-serine, L-threonine, 3-(1-naphthyl)-L-alanine, 3-(2-naphthyl)-L-alanine, N-isopropyl-glycine, xcex2-cyclohexyl-L-alanine or L-proline, particularly L-valine or L-phenylglycine, and l being zero and k being 1.
A preferred embodiment of the invention comprises compounds of formula I in which A is carbonyl.
A further preferred embodiment of the invention comprises compounds of formula I in which A is sulphonyl and R2 corresponds to formula VIa. Especially preferred are the compounds of formula I in which A is sulphonyl, R2 corresponds to formula VIa, d is 1 and e is zero.
Also preferred are compounds of formula I in which B is hydrogen or alkyl and especially those in which B is hydrogen or methyl. In a particularly preferred embodiment B is hydrogen.
A group of preferred compounds of formula I comprises those in which 
R2 is 
R3 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl or heteroaryl,
R4 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl,
R5, R6, R7and R8 are each independently hydrogen, alkyl or cycloalkyl or R7 and R8 together with the N atoms to which they are attached form a 5- to 8-membered heterocyclic ring which can be mono- or multiply-substituted by alkyl,
R9 is hydrogen, alkyl or cycloalkyl,
R10 is aryl, aralkyl or heterocyclyl, or R10 is an xcex1-amino acid bonded via the amino group, with l being zero and k being 1,
A is carbonyl or sulphonyl,
a to l are zero or whole positive numbers, with a being zero to 2, but not being zero when R1 is xe2x80x94NH2, b being zero to 4, c, d, f, g, k and l each independently being zero or 1 and c, f and g not all three simultaneously being zero, i being zero or 1 and k and l being zero when i is zero, e is zero to 3, h is zero to 5, j is zero to 2 and the sum of e, h and j is 2 to 7 and pharmaceutically salts and esters thereof.
A further group of preferred compounds of formula I comprises those in which
R1 is 
R2 is a substituent defined by formula III, IVa, IVb, V, VIa, VIb, VIc or VId, whereby in formulas VIb and VIc g is 1 when c is zero,
R3 is hydrogen, alkyl, cycloalkyl, carboxy, alkyl-Oxe2x80x94COxe2x80x94 or substituted or unsubstituted phenyl, with substituted phenyl being mono- or multiply-substituted by halogen, nitro and/or amino,
R4 is hydrogen, alkyl, cycloalkyl, phenyl or pyridyl,
R5 and R6 are hydrogen or pyridyl, preferably hydrogen, and R7 and R8 are hydrogen, or R5 and R6 are each hydrogen or pyridyl and R7 and R8 together with the N atoms to which they are attached form a 5- or 6-membered ring, especially an imidazolidine or hexahydropyrimidine ring,
R9 is hydrogen or cycloalkyl,
R10 is piperidyl, pyridylmethyl, pyridyl, benzyl, alkyl, hydrogen or substituted or unsubstituted phenyl, with the substituted phenyl being mono- or multiply-substituted by halogen, alkoxy, alkoxycarbonyl, carboxy or hydroxy, or R10 is alkyl-Oxe2x80x94CO-methyl, carboxymethyl, alkylsulphonyl, alkyl-COxe2x80x94, benzyl-Oxe2x80x94COxe2x80x94or alkyl-Oxe2x80x94COxe2x80x94O, with k being zero, or R10 is an xcex1-amino acid bonded via the amino group, with l being zero and k being 1, and especially R10 is L-valine, L-phenylalanine, L-phenylglycine, L-leucine, L-isoleucine, L-serine, L-threonine, 3-(1-naphthyl)-L-alanine, 3-(2-naphthyl)-L-alanine, N-isopropyl-glycine, xcex2-cyclohexyl-L-alanine or L-proline and l is zero and k is 1,
B is hydrogen or alkyl and
arylene signifies phenylene or substituted phenylene, with the phenylene being optionally mono- or multiply-substituted by alkoxy, alkoxy-alkoxy, halogen or aralkoxy.
A group of especially preferred compounds of formula I comprises those in which
R1 is 
R2 is a substituent defined by formula III, IVa, IVb, V, VIa, VIb, VIc or VId, whereby in formulas VIb and VIc g is 1 when c is zero,
R3 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, cyclopentyl, methyl-Oxe2x80x94COxe2x80x94, carboxy, phenyl, nitrophenyl or aminophenyl,
R4 is hydrogen, alkyl, phenyl or pyridin-2-yl,
R5, R6, R7 and R8 are hydrogen,
R9 is hydrogen or cyclopropyl,
R10 is piperidyl, pyridylmethyl, pyridyl, benzyl, alkyl, hydrogen or substituted or unsubstituted phenyl, with the substituted phenyl being mono- or multiply-substituted by halogen, alkoxy, alkoxycarbonyl, carboxy or hydroxy, or R10 is alkyl-Oxe2x80x94CO-methyl, carboxymethyl, alkylsulphonyl, alkyl-COxe2x80x94, benzyl-Oxe2x80x94COxe2x80x94or alkyl-Oxe2x80x94COxe2x80x94, with k being zero, or R10 is L-valine or L-phenylglycine and l being zero and k being 1,
B is hydrogen or methyl and
arylene signifies meta- or para-phenylene or substituted meta- or para-phenylene, with the substituents of the phenylene previously given by the definition of R2 standing meta- or para- to one another and the substituted phenylene carrying on the ring an additional substituent selected from the group of alkoxy, alkoxy-alkoxy, halogen and aralkoxy.
A preferred substitution pattern on the thiazole ring comprises the above compounds in which R2 is arranged on position 5 and R3 is arranged on position 4 of the thiazole rings. This applies especially when R2 represents a substituent of formula III, IVa, IVb or V.
Examples of preferred compounds of formula I are:
Ethyl 3-[3-[(2-guanidino-4methyl-thiazole-5-carbonyl)-amino]-propionylamino]-propionate,
3-[3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-propionylamino]-propionic acid hydrochloride,
ethyl 3-[3-[(2-guanidino-thiazole-4-carbonyl)-amino]-propionylamino]-propionate,
3-[3-[(2-guanidino-thiazole-4-carbonyl)-amino]-propionylamino]-propionic acid hydrochloride,
3-[3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-benzoylamino]-propionic acid trifluoroacetate,
ethyl rac 3-[3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-benzoylamino]-3-phenyl-propionate,
rac 3-[3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-benzoylamino]-3-phenyl-propionic acid hydrochloride,
ethyl rac 3-[2-[(2-guanidino-thiazole-5-carbonyl)-amino]-acetylamino]-3-phenyl-propionate,
rac 3-[2-[(2-guanidino-thiazole-5-carbonyl)-amino]-acetylamino]-3-phenyl-propionic acid hydrochloride,
ethyl rac-6-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-3-phenyl-hexanoate,
rac-6-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-3-phenyl-hexanoic acid,
ethyl rac-6-[(2-guanidino-thiazole-4-carbonyl)-amino]-3-phenyl-hexanoate,
rac-6-[(2-guanidino-thiazole-4-carbonyl)-amino]-3-phenyl-hexanoic acid,
ethyl rac-3-{3-[(2-guanidino-thiazole-4-carbonyl)-amino]-benzoylamino}-3-phenyl-propionate,
rac-3-{3-[(2-guanidino-thiazole-4-carbonyl)-amino]-benzoylamino}-3-phenyl-propionic acid,
3-[3-[(2-guanidino-thiazole-4-carbonyl)-amino]-benzoylamino]-propionic acid trifluoroacetate,
tert-butyl 3-[3-[(2-guanidino-thiazole-4-carbonyl)-amino]-benzoylamino]-propionate,
(S)-N-2-{2-[(2-guanidino-thiazole-4-carbonyl)-amino]-acetyl}-aspartic acid 1-N-phenyl-amide,
ethyl rac-3-[2-[(2-guanidino-thiazole-4-carbonyl)-amino]-acetylamino]-3-phenyl-propionate,
rac-3-[2-[(2-guanidino-thiazole-4-carbonyl)-amino]-acetylamino]-3-phenyl-propionic acid hydrochloride,
ethyl rac-3-[3-[(2-guanidino-thiazole-4-carbonyl)-amino]-propionylamino]-3-phenyl-propionate,
rac-3-[3-[(2-guanidino-thiazole-4-carbonyl)-amino]-propionylamino]-3-phenyl-propionic acid,
ethyl rac-3-[3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-propionylamino]-3-phenyl-propionate,
rac-3-[3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-propionylamino]-3-phenyl-propionic acid,
[2-guanidino-thiazole-4-carbonyl]-Gly-Asp-Val-OH hydrochloride,
ethyl 3-[2-[(2-guanidino-thiazole-4-carbonyl)-amino]-acetylamino]-propionate,
3-[2-[(2-guanidino-thiazole-4-carbonyl)-amino]-acetylamino]-propionic acid,
N-[4-(2-guanidino-4-methyl-thiazol-5-yl)-phenyl]-succinamic acid monoamide,
N-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenyl]-succinamic acid monoamide,
rac 4-[4-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-3-phenyl-butyric acid,
rac 4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-3-phenyl-butyric acid,
methyl 5-[4-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-pentanoate,
methyl 5-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-pentanoate,
5-[4-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-pentanoic acid,
5-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-pentanoic acid,
ethyl rac 3-(4-chloro-phenyl)-4-[4-(2-guanidino-4-methyl-thiazol-5-yl)-benzoylamino]-butyrate,
ethyl rac 3-(4-chloro-phenyl)-4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-benzoylamino]-butyrate,
ethyl rac 3-[4-(2-guanidino-4-methyl-thiazol-5-yl)-benzoylamino]-3-phenyl-propionate,
ethyl rac 3-[3-(2-guanidino-4-methyl-thiazol-5-yl)-benzoylamino]-3-phenyl-propionate,
rac 3-(4-chloro-phenyl)-4-[4-(2-guanidino-4-methyl-thiazol-5-yl)-benzoylamino]-butyric acid,
rac 3-(4-chloro-phenyl)-4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-benzoylamino]-butyric acid,
rac 3-[4-(2-guanidino-4-methyl-thiazol-5-yl)-benzoylamino]-3-phenyl-propionic acid,
rac 3-[3-(2-guanidino-4-methyl-thiazol-5-yl)-benzoylamino]-3-phenyl-propionic acid,
ethyl rac 3-[2-[(2-guanidino-4-methyl-thiazol-5-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionate hydrochloride,
ethyl rac 3-[2-[(2-guanidino-4-propyl-thiazol-5-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionate,
ethyl rac 3-[2-[(2-guanidino-4-phenyl-thiazol-5-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionate,
ethyl rac 3-[2-[(4-tert-butyl-2-guanidino-thiazol-5-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionate,
ethyl rac 3-[2-[[2-(tert-butoxycarbonylamino-methyl)-thiazol-4-ylcarbonyl]-amino]-acetylamino]-3-phenyl-propionate,
ethyl rac 3-[2-[(2-aminomethyl-thiazol-4-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionate hydrochloride,
ethyl rac 3-[2-[(2-guanidinomethyl-thiazol-4-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionate hydrochloride,
rac 3-[2-[(2-guanidino-4-methyl-thiazol-5-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionic acid,
rac 3-[2-[(2-guanidino-4-propyl-thiazol-5-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionic acid,
rac 3-[2-[(2-guanidino-4-phenyl-thiazol-5-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionic acid,
rac 3-[2-[(4-tert-butyl-2-guanidino-thiazol-5-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionic acid,
rac 3-[2-[(2-aminomethyl-thiazol-4-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionic acid,
rac 3-[2-[(2-guanidinomethyl-thiazol-4-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionic acid,
ethyl rac 3-[2-[[(2-(3-benzyl-ureido)-thiazol-4-ylcarbonyl]-amino]-acetylamino]-3-phenyl-propionate,
ethyl rac 3-[3-[(4-tert-butyl-2-guanidino-thiazol-5-ylcarbonyl)-amino]-benzoylamino]-3-pyridin-3-yl-propionate,
ethyl rac 3-[3-[[4-methyl-2-(3-methyl-ureido)-thiazol-5-ylcarbonyl]-amino]-benzoyl-amino]-3-pyridin-3-yl-propionate,
ethyl rac 3-[2-[Cyclopropyl-(2-guanidino-4-methyl-thiazol-5-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionate hydrochloride,
tert-butyl (S)-3-[2-[(2-guanidino-4-methyl-thiazol-5-ylcarbonyl)-amino]-acetylamino]-4-oxo-4-piperidin-1-yl-butyrate,
ethyl 3-[2-[(2-guanidino-4-methyl-thiazol-5-ylcarbonyl)-amino]-acetylamino]-propionate,
rac 3-[2-[[(2-(3-benzyl-ureido)-thiazol-4-ylcarbonyl]-amino]-acetylamino]-3-phenyl-propionic acid,
rac 3-[3-[(4-tert-butyl-2-guanidino-thiazol-5-ylcarbonyl)-amino]-benzoylamino]-3-pyridin-3-yl-propionic acid,
rac 3-[3-[[4-methyl-2-(3-methyl-ureido)-thiazol-5-ylcarbonyl]-amino]-benzoylamino]-3-pyridin-3-yl-propionic acid,
rac 3-[2-[cyclopropyl-(2-guanidino-4-methyl-thiazol-5-ylcarbonyl)-amino]-acetyl-amino]-3-phenyl-propionic acid,
3-[2-[(2-guanidino-4-methyl-thiazol-5-ylcarbonyl)-amino]-acetylamino]-propionic acid,
(S)-3-[2-[(2-guanidino-4-methyl-thiazol-5-ylcarbonyl)-amino]-acetylamino]-4-oxo-piperidin-1-yl-butyric acid,
tert-butyl (S)-3-[2-[(2-guanidino-thiazol-4-ylcarbonyl)-amino]-acetylamino]-4-oxo-4-piperidin-1-yl-butyrate,
(S)-3-[2-[(2-guanidino-thiazol-4-ylcarbonyl)-amino]-acetylamino]-4-oxo-4-piperidin-1-yl-butyric acid,
ethyl rac 3-[3-[(2-guanidino-4-methyl-thiazol-5-ylcarbonyl)-amino]-phenyl-sulphonyl-amino]-3-phenyl-propionate,
rac 3-[3-[(2-guanidino-4-methyl-thiazol-5-ylcarbonyl)-amino]-phenylsulphonylamino]-3-phenyl-propionic acid,
rac 4-[3-(2-guanidino-thiazol-4-yl)-phenylcarbamoyl]-3-phenyl-butyric acid,
rac 3-(4-chloro-phenyl)-4-[3-(2-guanidino-thiazol-4-yl)-benzoylamino]-butyric acid,
rac 4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-3-(4-methoxy-phenyl)-butyric acid,
ethyl rac-3-[5-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-2-(2-methoxy-ethoxy)-benzoylamino]-3-phenyl-propionate,
rac-3-[5-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-2-(2-methoxy-ethoxy)-benzoylamino]-3-phenyl-propionic acid hydrochloride,
ethyl rac-3-{3-[(2-guanidino-thiazole-5-carbonyl)-amino]-benzoylamino}-3-phenyl-propionate,
rac-3-[3-[(2-guanidino-thiazole-5-carbonyl)-amino]-benzoylamino]-3-phenyl-propionic acid,
ethyl rac-3-{3-benzyloxy-5-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-benzoylamino}-3-phenyl-propionate,
rac-3-{3-benzyloxy-5-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-benzoylamino}-3-phenyl-propionic acid,
ethyl rac-7-{[2-(3-benzyl-ureido)-4-methyl-thiazole-5-carbonyl]-amino}-3-phenyl-heptanoate,
rac-7-{[2-(3-benzyl-ureido)-4-methyl-thiazole-5-carbonyl]-amino}-3-phenyl-heptanoic acid,
ethyl rac-3-{3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-4-methoxy-benzoylamino}-3-phenyl-propionate,
rac-3-{3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-4-methoxy-benzoylamino}-3-phenyl-propionic acid hydrochloride,
ethyl rac-3-{2-[(2-guanidino-thiazole-4-carbonyl)-amino]-acetylamino}-3-pyridin-3-yl-propionate,
rac-3-{2-[(2-guanidino-thiazole-4-carbonyl)-amino]-acetylamino}-3-pyridin-3-yl-propionic acid,
ethyl 6-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-5-oxo-hexanoate,
6-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-5-oxo-hexanoic acid,
ethyl rac-7-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-3-phenyl-heptanoate,
rac-7-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-3-phenyl-heptanoic acid,
(S)-3-(2-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-acetylamino)-succinic acid 4-anilide 1-tert-butyl ester,
(S)-3-(2-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-acetylamino)-succinic acid 4-anilide,
rac 4-{3-[2-(3-benzyl-ureido)-4-methyl-thiazol-5-yl]-phenylcarbamoyl}-3-phenyl-butyric acid,
rac 4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-3-pyridin-3-yl-butyrate,
rac 4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-3-pyridin-3-yl-butyric acid,
rac-4-[3-(4-ethyl-2-guanidino-thiazol-5-yl)-phenylcarbamoyl]-3-phenyl-butyric acid acetate,
rac-4-[3-(2-guanidino-4-propyl-thiazol-5-yl)-phenylcarbamoyl]-3-phenyl-butyric acid,
rac-4-[3-(4-butyl-2-guanidino-thiazol-5-yl)-phenylcarbamoyl]-3-phenyl-butyric acid,
rac-4-[3-(2-guanidino-4-pentyl-thiazol-5-yl)-phenylcarbamoyl]-3-phenyl-butyric acid,
rac-3-(4-chloro-phenyl)-4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-butyric acid,
rac-4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-3-hydroxy-butyric acid,
4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-butyric acid,
rac-4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-3-methyl-butyric acid,
rac-3-(3-bromo-phenyl)-4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-butyric acid,
rac-3-(3,5-dichloro-2-hydroxy-phenyl)-4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-butyric acid,
rac-4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-3-(3-methoxy-phenyl)-butyric acid,
rac-4-[4-chloro-3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-3-phenyl-butyric acid,
rac-4-[2-chloro-5-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-3-phenyl-butyric acid
(S)-2-butylsulphonylamino-4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-benzoylamino]-butyric acid hydrochloride,
ethyl rac-3-[3-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenyl]-ureido]-3-phenyl-propionate,
rac-3-[3-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenyl]-ureido]-3-phenyl-propionic acid,
ethyl rac-4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-3-phenyl-butyrate hydrochloride,
rac-4-[[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenyl]-methyl-carbamoyl]-3-phenyl-butyric acid,
methyl rac-4-benzyloxycarbonylamino-4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-butyrate,
rac-4-benzyloxycarbonylamino-4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenyl-carbamoyl]-butyric acid,
methyl rac-5-[3-(4-carboxy-3-phenyl-butyrylamino)-phenyl]-2-guanidino-thiazole-4-carboxylate,
rac-5-[3-(4-carboxy-3-phenyl-butyrylamino)-phenyl]-2-guanidino-thiazole-4-carboxylic acid,
ethyl rac-3-[2-[(2-guanidino-5-methyl-thiazol-4-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionate,
ethyl rac-3-[2-[(5-tert-butyl-2-guanidino-thiazol-4-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionate,
ethyl rac-3-[2-[(2-guanidino-5-phenyl-thiazol-4-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionate,
ethyl rac-3-[2-[[2-guanidino-5-(3-nitro-phenyl)-thiazol-4-ylcarbonyl]-amino]-acetyl-amino]-3-phenyl-propionate,
rac-3-[2-[(2-guanidino-5-methyl-thiazol-4-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionic acid,
rac-3-[2-[(5-tert-butyl-2-guanidino-thiazol-4-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionic acid,
rac-3-[2-[(2-guanidino-5-phenyl-thiazol-4-ylcarbonyl)-amino]-acetylamino}-3-phenyl-propionic acid,
rac-3-[2-[2-guanidino-5-(3-nitro-phenyl)-thiazol-4-ylcarbonyl]-amino]-acetylamino]-3-phenyl-propionic acid,
rac-3-[2-[[5-(3-amino-phenyl)-2-guanidino-thiazol-4-ylcarbonyl]-amino]-acetyl-amino]-3-phenyl-propionic acid,
ethyl rac-3-[2-[[2-(3-benzyl-ureido)-5-methyl-thiazol-4-ylcarbonyl]-amino]-acetylamino ]-3-phenyl-propionate,
ethyl rac-3-[2-[[2-(3-benzyl-ureido)-5-phenyl-thiazol-4-ylcarbonyl]-amino]-acetylamino]-3-phenyl-propionate,
rac-3-[2-[[2-(3-benzyl-ureido)-5-methyl-thiazol-4-ylcarbonyl]-amino]-acetylamino]-3-phenyl-propionic acid,
rac-3-[2-[[2-(3-benzyl-ureido)-5-phenyl-thiazol-4-ylcarbonyl]-amino]-acetylamino]-3-phenyl-propionic acid,
rac-4-[3-[2-(3-benzyl-ureido)-5-methyl-thiazol-4-yl]-phenylcarbamoyl]-3-phenyl-butyric acid,
rac-4-[[3-[2-(3-benzyl-ureido)-5-methyl-thiazol-4-yl]-phenyl]-methyl-carbamoyl]-3-phenyl-butyric acid,
ethyl rac-3-phenyl-3-[2-[[2-(3-phenyl-ureido)-thiazol-4-ylcarbonyl]-amino]-acetyl-amino]-propionate,
ethyl rac-3-[2-[[2-(3-Phenethyl-ureido)-thiazol-4-ylcarbonyl]-amino]-acetylamino]-3-phenyl-propionate,
ethyl rac-3-(2-[[2-(3-butyl-ureido)-thiazol-4-ylcarbonyl]-amino]-acetylamino)-3-phenyl-propionate,
rac-3-phenyl-3-[2-[[2-(3-phenyl-ureido)-thiazol-4-ylcarbonyl]-amino]-acetylamino]-3-propionic acid,
rac-3-[2-[[2-(3-Phenethyl-ureido)-thiazol-4-ylcarbonyl]-amino]-acetylamino]-3-phenyl-propionic acid,
rac-3-(2-[[2-(3-butyl-ureido)-thiazol-4-ylcarbonyl]-amino]-acetylamino)-3-phenyl-propionic acid,
ethyl rac-3-[4-[[2-(3-benzyl-ureido)-thiazol-4-ylcarbonyl]-amino]-phenyl]-3-tert-butoxycarbonylamino-propionate,
rac-3-[4-[[2-(3-benzyl-ureido)-thiazol-4-ylcarbonyl]-amino]-phenyl]-3-tert-butoxy-carbonylamino-propionic acid,
rac-3-amino-3-[4-[[2-(3-benzyl-ureido)-thiazol-4-ylcarbonyl]-amino]-phenyl]-propionic acid,
ethyl rac-3-[4-[[2-(3-benzyl-ureido)-thiazol-4-ylcarbonyl]-amino]-phenyl]-3-propionyl-amino-propionate,
ethyl rac-3-[4-[[2-(3-benzyl-ureido)-thiazol-4-ylcarbonyl]-amino]-phenyl]-3-butyl-sulphonylamino-propionate,
rac-3-[4-[[2-(3-benzyl-ureido)-thiazol-4-ylcarbonyl]-amino]-phenyl]-3-propionyl-amino-propionic acid,
rac-3-[4-[[2-(3-benzyl-ureido)-thiazol-4-ylcarbonyl]-amino]-phenyl]-3-butylsuphonyl-amino-propionic acid,
diethyl 3-[4-[[2-(3-benzyl-ureido)-thiazol-4-ylcarbonyl]-amino]-phenyl]-glutarate,
3-[4-[[2-(3-benzyl-ureido)-thiazol-4-ylcarbonyl]-amino]-phenyl]-glutaric acid,
rac-4-[3-[2-(Nxe2x80x2-benzyl-guanidino)-4-methyl-thiazol-5-yl]-phenylcarbamoyl]-3-phenyl-butyric acid,
ethyl rac-3-phenyl-3-[2-[[2-(pyridin-2-ylamino)-thiazol-4-ylcarbonyl]-amino]-acetyl-amino]-propionate,
rac-3-phenyl-3-[2-[[2-(pyridin-2-ylamino)-thiazol-4-ylcarbonyl]-amino]-acetylamino]-propionic acid,
ethyl rac-3-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetylamino]-3-pyridin-3-yl-propionate,
rac-3-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetylamino]-3-pyridin-3-yl-propionic acid acetate,
tert-butyl (S)-N-benzyl-3-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetylamino]-succinamate,
ethyl 3-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetylamino]-propionate,
3-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetylamino]-propionic acid hydrochloride,
tert-butyl (S)-3-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetylamino]-N-(3-methoxy-phenyl)-succinamate,
(S)-3-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetylamino]-N-(3-methoxy-phenyl)-succinamic acid,
tert-butyl (S)-2-[2-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetylamino]-3-tert-butoxycarbonyl-propionylamino]-benzoate,
(S)-2-[2-(2-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-acetylamino)-3-carboxy-propionylamino]-benzoic acid,
methyl 6-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-hexanoate,
6-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-hexanoic acid,
tert-butyl (S)-3-[3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-benzoyl-amino]-N-phenyl-succinamate,
(S)-3-[3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-benzoylamino]-N-phenyl-succinamic acid trifluoroacetate,
tert-butyl (S)-2-[(S)-2-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetyl-amino]-3-tert-butoxycarbonyl-propionylamino]-3-methyl-butyrate,
tert-butyl (S)-3-[(S)-2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetyl-mino]-N-(tert-butoxycarbonyl-phenyl-methyl)-succinamate,
(S)-3-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetylamino]-N-[(S)-carboxy-phenyl-methyl)-succinamic acid acetate/trifluoroacetate,
methyl (S)-6-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-2-tert-butoxycarbonylamino-hexanoate,
(S)-6-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-2-tert-butoxycarbonylamino-hexanoic acid,
ethyl rac-3-benzylcarbamoyl-6-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-hexanoate,
rac-3-benzylcarbamoyl-6-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-hexanoic acid,
ethyl 5-oxo-6-{[2-(3-pyridin-2-ylmethyl-ureido)-thiazole-4-carbonyl]-amino}-hexnoate,
5-oxo-6-{[2-(3-pyridin-2-ylmethyl-ureido)-thiazole-4-carbonyl]-amino}-hexanoic acid hydrochloride,
tert-butyl (S)-N-benzyl-3-{4-[2-(3-benzyl-ureido)-thiazol-4-yl]-butyrylamino}-succinamate,
(S)-N-benzyl-3-{4-[2-(3-benzyl-ureido)-thiazol-4-yl]-butyrylamino}-succinamic acid trifluoroacetate,
ethyl 3-[4-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-phenyl]-propionate,
3-[4-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-phenyl]-propionic acid,
diethyl rac-2-[3-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-2-oxo-propyl]-succinate,
rac-2-[3-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-2-oxo-propyl]-succinic acid,
di-tert-butyl (S)-2-(2-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-acetylamino)-succinate,
(S)-2-(2-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-acetylamino)-succinic acid trifluoroacetate,
tert-butyl (S)-3-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetylamino]-N-isobutyl-succinamate,
tert-butyl (S)-3-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetylamino]-N-pyridin-2-ylmethyl-succinamate,
tert-butyl (S)-3-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetylamino]-N-pyridin-3-ylmethyl-succinamate,
(S)-3-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetylamino]-N-pyridin-3-ylmethyl-succinamic acid trifluoroacetate,
(S)-3-[4-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-phenyl]-2-tert-butoxy-carbonylamino-propionic acid,
(R)-3-[4-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-phenyl]-2-tert-butoxy-carbonylamino-propionic acid,
tert-butyl (S)-N-pyridin-2-ylmethyl-3-(2-{[2-(3-pyidin-2-ylmethyl-ureido)-thiazole-4-carbonyl]-amino}-acetylamino)-succinamate,
(S)-N-pyridin-2-ylmethyl-3-(2-{[2-(3-pyridin-2-ylmethyl-ureido)-thiazole-4-carbonyl]-amino}-acetylamino)-succinamic acid,
tert-butyl 3-(3-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-benzoylamino)-propionate,
3-(3-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-benzoylamino)-propionic acid,
ethyl rac-3-(2-{[2-(imidazolidin-2-ylideneamino)-thiazole-4-carbonyl]-amino}-acetyl-amino)-3-pyridin-3-yl-propionate,
3-(2-{[2-(imidazolidin-2-ylideneamino)-thiazole-4-carbonyl]-amino}-acetylamino)-3-pyridin-3-yl-propionic acid hydrochloride,
ethyl rac-7-[[4-methyl-2-(tetrahydro-pyrimidin-2-ylideneamino)-thiazole-5-carbonyl]-amino]-3-phenyl-heptanoate and
rac-7-[[4-methyl-2-(tetrahydro-pyrimidin-2-ylideneamino)-thiazole-5-carbonyl]-amino]-3-phenyl-heptanoic acid hydrochloride acetate.
Examples of especially preferred compounds of formula I are:
rac 3-[2-[[2-(3-Benzyl-ureido)-thiazol-4-ylcarbonyl]-amino]-acetylamino]-3-phenyl-propionic acid,
rac 4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-3-phenyl-butyric acid,
rac 3-[2-[(2-guanidinomethyl-thiazol-4-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionic acid,
rac 3-[3-[(2-guanidino-4-methyl-thiazol-5-ylcarbonyl)-amino]-phenylsulphonyl-amino]-3-phenyl-propionic acid,
rac 3-[3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-benzoylamino]-3-phenyl-propionic acid hydrochloride,
rac 3-[3-[(4-tert-buty]-2-guanidino-thiazol-5-ylcarbonyl)-amino]-benzoylamino]-3-pyridin-3-yl-propionic acid,
[2-guanidino-thiazole-4-carbonyl]-Gly-Asp-Val-OH hydrochloride,
rac 3-(4-chloro-phenyl)-4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-benzoylamino]-butyric acid,
rac-3-[3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-propionylamino]-3-phenyl-propionic acid,
rac 4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-3-(4-methoxy-phenyl)-butyric acid,
rac 4-[3-(2-guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-3-pyridin-3-yl-butyric acid,
6-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-5-oxo-hexanoic acid,
(S)-3-(2-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino }-acetylamino)-succinic acid 4-anilide,
(S)-N-benzyl-3-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetylamino]-succinamic acid trifluoroacetate,
(S)-2-[(S)-2-(2-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-acetylamino)-3-carboxy-propionylamino]-3-methyl-butyric acid acetate/trifluoroacetate,
(S)-3-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetylamino]-N-isobutyl-succinamic acid trifluoroacetate and
(S)-3-[2-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetylamino]-N-pyridin-ylmethyl-succinamic acid trifluoroacetate.
Processes for the manufacture of compounds of formula of I are an object of the invention. The processes are preferably based on the reaction of a thiazole derivative, which represents the thiazole base member, with a reactive reagent, which represents the substituent R2 or a reactive part and/or derivative thereof.
The following routes can be set out, for example, for the preparation of the corresponding thiazole base member, with the substituents and indices used in the following Schemes having the significances given above unless indicated to the contrary.
Suitable thiazole base members can be prepared, for example, by the method presented in Scheme 1a. In this, an xcex1-bromo-ketone of formula VII, such as ethyl pyruvate, is reacted in a solvent, such as ethanol, with a thiourea derivative of formula VIII, such as 2-imino-4-thiobiuret, at elevated temperature [J. Med. Chem., 34: 914 (1991)]. A subsequent saponification of the ester group by means of a base, such as aqueous NaOH or KOH, yields a thiazole-4-carboxylic acid of type X (Scheme 1a).
In a process variant an optionally substituted thiourea of formula IX is used and, after cyclization to the thiazole, is reacted with an isocyanate, such as benzyl isocyanate, in a solvent, such as DMF, at room temperature, followed by a saponification of the ester as described above. 
xcex1-Halo-ketones are used in a further preparative process (Scheme 1b), which analogously to the process described yields thiazole-5-carboxylic acid derivatives of type XIII [Farmaco, 44: 1011(1989)]. The xcex1-halo-ketones of formula XII are prepared from the corresponding xcex2-keto esters (formula XI), such as ethyl butyrylacetate, ethyl pivaloylacetate, etc., by halogenation with e.g. bromine in a solvent, such as water, conveniently at a temperature of 0-5xc2x0 C. (J. Chem. Soc. Perkin I 1982, 162). 
In another variant (Scheme 1c) the thiazole base member is synthezised by reaction of a N-protected amino acid thioamide optionally substituted on the amino nitrogen, such as N-Boc-glycine thioamide, with an xcex1-halo-ketone of formula VII or XIb. A subsequent saponification of the ester group by means of a base, as described under Scheme 1a, yields thiazolecarboxylic acid derivatives of formula XIV. After removal of the protecting group these can be modified further in accordance with Scheme 10.
When a residue ((CH2)exe2x80x94NHxe2x80x94(protecting group) is used in place of the COOR01 residue in compound XIb or XII, then amino-thiazole derivatives corresponding to XIII can be obtained. The analogous situation also applies to Scheme 1a. 
In an additional process variant (Scheme 1d) a substituted benzaldehyde, such as 3-nitrobenzaldehyde, or methyl 3-formyl-benzoate, is converted with a nitroalkane, such as nitroethane, in a suitable solvent, such as acetic acid, with the addition of ammonium acetate, conveniently at elevated temperature, such as reflux temperature, into the corresponding nitro-olefin (Org. Synth. Coll. IV, 573 or Synthesis 1994, 258). This is epoxidized by means of an oxidation agent, such as hydrogen peroxide, in a suitable solvent, such as water, with the addition of aqueous sodium hydroxide solution to give a nitroepoxide of formula XV (Synthesis 1976, 53). The reaction of such nitroepoxide with a thiourea derivative, such as 2-imino-4-thiobiuret, at elevated temperature, such as the reflux temperature, yields arylthiazoles of formula XVI.
By the use of an alternative thiourea derivative in the above reaction and subsequently reaction with an isocyanate, such as benzyl isocyanate, in a solvent, such as DMF, at room temperature there are obtained arylthiazoles of formula XVII, into which subsequently an additional substituent R5 can be introduced by usual methods. 
When using 
in place of compound XV in Scheme 1d there is obtained the compound corresponding to XVI and XVII in which, however, the arylene residue is bonded to position 4 of the thiazole and R3 is bonded to position 5 of the thiazole ring.
In order to prepare compounds analogous to XVI to XVII, with e being other than zero in accordance with formula (I), in place of the thiourea derivative used in Scheme 1d there can be used, for example, the thioamide used as the starting material in Scheme 1c.
The thiazole base members obtainable in accordance with the above processes are converted in a subsequent reaction with reactive components and/or reactive derivatives of the R2 substituent to give a compound of general formula I in one or more reaction steps.
In the cases where c is equal to 1, i.e. an amide bond is present on the thiazole structure, a corresponding thiazolecarboxylic acid can be reacted with a corresponding amine to give a compound of formula I according to known methods. In principle, the following route can be set out:
In the following process variant (Scheme 2) by coupling a thiazolecarboxylic acid of formula XXXI with an amine of formula XXXVII using BOP, HBTU or CDMT and with subsequent hydrolysis of the ester function there is prepared the desired thiazole I in this connection, see also Z. J. Kaminski, Synthesis, 1987, 917. 
For example, when f equals zero and g equals 1 the following process can be used for the manufacture of compounds of formula I:
A thiazolecarboxylic acid of formula XXXI (Scheme 3) is coupled with a amine of formula XXXII by means of a usual coupling reagent, such as HBTU CDMT, etc., in the presence of a base, such as N-methylmorpholine, in a solvent, such as DMF or THF. A subsequent hydrolysis by means of a strong base, such as NaOH in a solvent, such as water-ethanol, yields the thiazole acid XXXIV. This is reacted with amine XXXV in a further coupling using HBTU or CDMT and subsequently hydrolyzed to XXXVI by ester cleavage using strong acid, such as trifluoroacetic acid in methylene chloride or aqueous hydrochloric acid, or using a strong base, such as NaOH. 
The preparation of the corresponding amine components is effected according to methods known per se. When g and f in general formula I are not equal, the amide or sulphonamide bonding which then occurs can be achieved, for example, by reaction of the corresponding amine component with an acid component according to known methods.
The following process can be used e.g. for the preparation of the amine component:
N-Protected amino acids XXI are (Scheme 4) coupled with an amino acid ester XXII by means of a coupling reagent, such as CDMT, in the presence of a base, such as N-methylmorpholine, in a suitable solvent, such as THF. N-Protecting groups, such as BOC, are then cleaved off with HCl in ethyl acetate or with trifluoroacetic acid and those such as Cbz are cleaved off by catalytic hydrogenation, e.g. on Pd/C in a solvent, such as ethanol, to give compounds of type XXIII. 
For example, other amine components (formula XXV; Scheme 5a) can be prepared by coupling an optionally substituted, N-protected aminobenzoic acid XXIV with an amino acid ester XXII using a coupling reagent, such as CDMT or BOP, in the presence of a base, such as NMM or N-ethyl-morpholine, in a suitable solvent, such as DMF or THF, at RT or, if necessary, elevated temperature and subsequently removing the protecting groups as described in Scheme 4. 
Further amino components can be prepared e.g. as follows: Nitrosulphochlorides are reacted (Scheme 5b) with an amine component XXII in the presence of the strong base, such as aqueous NaOH, in a solvent, such as ether. Esterification of the free carboxylic acids followed by a reduction of the nitro group according to usual methods, such as hydrogen in the presence Raney-nickel as the catalyst, yields the anilino-esters XXVI. 
Further amine components can be prepared, for example, as follows: Intermediates XXX (Scheme 6a) are prepared by coupling an appropriate aspartic acid derivative, such as XXIX, with an amine HNRR1 using the methods already described. 
Compounds of formula XXXXII can be prepared as further intermediates. For this, amine components of formula XXXXI, the carboxylic acid function of which is protected suitably as an ester, are reacted with an acid chloride, such as phosgene or sulphuryl chloride, in the presence of a base, such as e.g. 4-ethylmorpholine, and in a suitable solvent, such as e.g. toluene. 
When f and g of general formula both equal zero, then the corresponding compound (A is xe2x80x94C(O)xe2x80x94) can be obtained according to known methods for the preparation of ketones [such as e.g. Biochem. Med., 17: 31-44 (1977)].
When A equals SO2, the corresponding sulphones are obtained by oxidation of the thioethers, which are prepared according to known methods, e.g. by reaction of a thiazole with the corresponding alkyl halide.
When f and g are both equal to 1, the compounds are corresponding ureas or sulphamides. The manufacture is effected when c is equal to zero by reaction of the compound XXXXII with the compounds e.g. of formula XVI and XVII reduced to the amine. When c is equal to 1, the acid chloride of formula XXXXII is reacted with a corresponding monoprotected diamine, which after cleavage of the protecting group is reacted with the thiazolecarboxylic acid of formula XXXI. Boc or Cbz comes into consideration, for example, as the protecting group. When d is equal to 1, i.e. arylene is present, then a corresponding diamine in which the arylene is already present is used.
Alternatively, the above compounds of general formula I can also be obtained by reaction of a reactive fragment of the amine described in Scheme 2 and subsequent addition of the still missing substituent part of R2.
When the compounds of formula I are substances in which c is equal to zero, then it is possible to proceed analogously to Scheme 2 with the formation of an amide bond. When f is equal to 1 and g is equal to zero or f is equal to zero and g is equal to 1, the corresponding compound of formula I can be manufactured by reaction of an amino aryl thiazole with an acid derivative (f equals 1 and g equals zero).
For example, the following methods can be used:
Reduction of the nitro-arylthiazoles of formula XVI (Scheme 7a) with a suitable reducing agent, such as hydrogen in the presence of a suitable catalyst, such as Raney-nickel, in a solvent, such as aqueous hydrochloric acid-methanol, or as an alternative, tin-II chloride in aqueous hydrochloric acid, preferably at elevated temperatures, such as 50xc2x0 C., yields the corresponding aniline derivative. This is reacted with a carboxylic acid anhydride, such as succinic acid anhydride, glutaric acid anhydride etc., in the presence of a base, such as 4-ethylmorpholine, in a solvent, such as DMF, at room temperature and yields a guanidino-arylthiazole of formula XVIII.
In a process variant the aniline derivative obtained after the reduction is reacted with a dicarboxylic acid protected as the mono-ester, such as mono-methyl adipate, under the influence of a coupling reagent, such as BOP, and a base, such as 4-ethylmorpholine, in a solvent, such as DMF, at room temperature, followed by an ester hydrolysis by means of a strong base, such as lithium hydroxide, in a suitable solvent, such as water-tetrahydrofuran, preferably at room temperature.
When Y is equal to xe2x80x94(CH2)exe2x80x94NH-(protecting group), then no reduction is required. The corresponding protecting group, for example Boc or Cbz, can be removed using usual methods (e.g. HCl in ethyl acetate). 
In a manner analogous to Scheme 7a, nitro-arylthiazoles of formula XVII are converted into the corresponding ureido-aryl-thiazoles of formula XIX (Scheme 7b).
Also analogously to Scheme 7a, the corresponding 4-(nitro-aryl)-2-ureido-thiazoles are reduce and acylated. Also here in the case where Y is equal to xe2x80x94(CH2)exe2x80x94NH-(protecting group) no reduction is required. When B is other than hydrogen, the corresponding amines, as described for Scheme 7a, are alkylated prior to the acylation with an aldehyde in the presence of NaBH4 or NaCNBH3. 
Also, compounds of the type 
can be used analogously to Schemes 7a and 7b, although in this case the amino group must be protected with e.g. Boc or Cbz.
When f is equal to zero and g is equal to 1, the corresponding compounds of formula I can be obtained by reaction of a thiazole acid derivative with an amine:
The carboxylic esters of the arylthiazoles of formula XVI and XVII (Scheme 1d) are hydrolyzed by means of a strong base, such as lithium hydroxide, in a suitable solvent, such as water-tetrahydrofuran, preferably at room temperature (Scheme 8). Coupling of the acids with an amine component, the carboxylic acid function of which is suitably protected as an ester, using a coupling reagent, such as BOP and a base, such as 4-ethylmorpholine, in a solvent, such DMF, at room temperature, followed by an ester hydrolysis using a strong base, such as lithium hydroxide, in a suitable solvent, such as water-tetrahydrofuran, preferably at room temperature, yields the guanidino-aryl-thiazoles of formula XX. When R1 is amino, this must be present as Boc- or Cbz-protected amino.
The carboxylic acid esters of the 2-ureido-aryl thiazoles of formula XVII are coupled and saponified in a manner analogous to Scheme 8. The corresponding 4-(hydroxycarbonylaryl)-thiazoles are reacted analogously. 
The corresponding aminoarylthiazoles and carboxyarylthiazoles are accessible e.g. by the reaction route set forth in Scheme 1d. The amine derivatives (g equals 1) or acid derivatives (f equals 1) required for the generation of the substituent R2 are obtainable according to methods known per se.
Compounds of the formula H2Nxe2x80x94R012 are commercially available or can be synthesized according to, for example, one of the following routes: when R10 is an amino acid bonded via the amino group and k is equal to 1 and l is equal to zero, the synthesis is effected according to usual methods and protecting group techniques as used in peptide synthesis. When R10 is aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydrogen or alkyl, with l being equal to 1 and k being equal to 1, the same procedure can be used. When k is equal to zero, l is equal to 1 and j is equal to 1, then the amine R10xe2x80x94NH2 can be added to the corresponding xcex1,xcex2-unsaturated carboxylic acid derivative in the sense of a Michael addition. The primary amines obtained in this manner can subsequently be derivatized by reaction with carboxylic acid chlorides or anhydrides, chloroformic acid esters or sulphochlorides according to conventional methods. Where k is equal to zero, l is equal to 1 and j is equal to zero, the corresponding xcex1-amino acids are commercially available or can be obtained according to syntheses described in the literature. Where k is equal to zero, l is equal to 1 and j is equal to 2, corresponding xcex3-keto esters can be used and can be converted into the desired amines by reductive amination with R10 xe2x80x94NH2. Where l is equal to zero and k is equal to 1, corresponding ketones can be prepared according to methods described by L. E. Fisher et al., Org. Prep. Proc. Int., 22: 399-484 (1990), or by K. Matsumoto et al., Chem. Pharm. Bull., 34: 4516 (1986). Where R10 is hydroxy, with l being equal to zero and k being equal to zero, an ester of the commercially available DL-4-amino-3-hydroxybutyric acid can, for example, be used. Where R10 is carboxyalkyl, the procedure described by O. Tsuge et al. [BulL Chem. Soc. Jpn. 59: 2537-45 (1986)] can be used.
Compounds of formula XXVII (Scheme 9) can be reacted e.g. with a Wittig-Horner reagent, such as triethyl phosphonoacetate, and a base, such as sodium alcoholate, in a solvent, such as ethanol, at RT or elevated temperature. The thereby obtained unsaturated compounds are hydrogenated on a catalyst, such a Pd/C, in a solvent, such as ethanol, and subsequently converted into the compounds XXVIII by removal of the protecting group. 
In addition to the processes described above, the substituent R1 can be varied in the scope of the definitions of general formula I. In this process variant (Scheme 10), a thiazole derivative of formula XXXVIII with intermediate protection of the acid functions in R2 and R3 can be guanidated [Tet. Lett., 29: 3183-86 (1988)]. Compound XXVIII is reacted with an isocyanate for the manufacture of the corresponding urea derivatives.
Compounds of the type XXXVIII can be obtained, for example, from compounds XIV after reaction with the corresponding amine components and removal of the Boc protecting group. When a is equal to zero, the procedure starts from corresponding thiazole base compounds of Schemes, 1a, 1b and 1d. 
In the case where m is equal to zero and f and g are equal to zero and c is equal to 1 the corresponding compounds can be prepared according to Scheme 2, wherein the substituent R2 is introduced by formation of an amide bond on the thiazole structure.
The invention also includes intermediates of the formulas 
and their salts in which R1, R3 and a have the previously given significance and wherein in formula XXXI R3 is not hydrogen or methyl when R1 is 
Especially preferred intermediates are:
Ethyl 2-guanidino-4-propyl-thiazole-5-carboxylate hydrobromide,
ethyl 2-guanidino-4-phenyl-thiazole-5-carboxylate hydrobromide,
ethyl 4-tert-butyl-2-guanidino-thiazole-5-carboxylate hydrobromide,
ethyl 4-cyclopentyl-2-guanidino-thiazole-5-carboxylate hydrobromide,
ethyl 3-(3-amino-benzoylamino)-3-phenyl-propionate hydrochloride,
ethyl rac-3-(2-benzyloxycarbonylamino-acetylamino)-3-phenyl-propionate,
ethyl rac-6-tert-butoxycarbonylamino-3-phenyl-hexanoate,
ethyl rac-6-amino-3-phenyl-hexanoate hydrochloride,
ethyl [(2-guanidino-thiazole-4-carbonyl)-amino]-acetate,
[(2-guanidino-thiazole-4-carbonyl)-amino]-acetic acid,
Cbz-(L)-aspartic acid 4-tert-butyl ester 1-N-phenyl-amide,
(L)-aspartic acid 4-tert-butyl ester 1-N-phenyl-amide,
ethyl rac-3-(3-benzyloxycarbonylamino-propionylamino)-3-phenyl-propionate,
ethyl rac-3-(3-amino-propionylamino)-3-phenyl-propionate,
2-guanidino-4-methyl-thiazole-5-carboxylic acid,
2-guanidino-4-propyl-thiazole-5-carboxylc acid hydrochloride,
2-guanidino-4-phenyl-thiazole-5-carboxylic acid,
4-tert-butyl-2-guanidino-thiazole-5-carboxylic acid hydrochloride,
4-cyclopentyl-2-guanidino-thiazole-5-carboxylic acid hydrochloride,
2-(tert-butoxycarbonylamino-methyl)-4-methyl-thiazole-5-carboxylic acid,
1-nitro-4-(2-nitro-propenyl)-benzene,
N-[4-methyl-5-(4-nitro-phenyl)-thiazol-2-yl]-guanidine,
N-[4-methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-guanidine,
methyl 4-(2-guanidino-4-methyl-thiazol-5-yl)-benzoate,
methyl 3-(2-guanidino-4-methyl-thiazol-5-yl)-benzoate,
N-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-guanidine hydrochloride,
N-[5-(3-amino-phenyl)-4-methyl-thiazol-2-yl]-guanidine hydrochloride,
4-(2-guanidino-4-methyl-thiazol-5-yl)-benzoic acid,
3-(2-guanidino-4-methyl-thiazol-5-yl)-benzoic acid,
4-methyl-2-(3-methyl-ureido)-thiazole-5-carboxylic acid,
ethyl 2-(3-benzyl-ureido)-4-methyl-thiazole-5-carboxylate,
2-(3-benzyl-ureido)-4-methyl-thiazole-5-carboxylic acid,
ethyl 2-(3-benzyl-ureido)-thiazole-4-carboxylate,
2-(3-benzyl-ureido)-thiazole-4-carboxylic acid,
ethyl rac 3-(3-tert-butoxycarbonylamino-benzoylamino)-3-pyridin-3-yl-propionate,
ethyl rac 3-(3-amino-benzoylamino)-3-pyridin-3-yl-propionate,
ethyl rac 3-[2-(tert-butoxycarbonyl-cyclopropyl-amino)-acetylamino]-3-phenyl-propionate,
ethyl rac 3-(2-cyclopropylamino-acetylamino)-3-phenyl-propionate hydrochloride,
rac 3-(3-nitro-phenylsulphonylamino)-3-phenyl-propionic acid,
ethyl rac 3-(3-nitro-phenylsulphonylamino)-3-phenyl-propionate,
ethyl rac 3-(3-amino-phenylsulphonylamino)-3-phenyl-propionate,
ethyl rac-3-[5-amino-2-(2-methoxy-ethoxy)-benzoylamino]-3-phenyl-propionate,
ethyl rac-3-(3-amino-5-benzyloxy-benzoylamino)-3-phenyl-propionate hydrochloride,
ethyl rac-7-tert-butoxycarbonylamino-3-phenyl-heptanoate,
ethyl rac-7-amino-3-phenyl-heptanoate hydrochloride,
ethyl rac-3-(3-amino-4-methoxy-benzoylamino)-3-phenyl-propionate,
ethyl 6-amino-5-oxo-hexanoate hydrochloride,
4-methyl-5-(3-nitro-phenyl)-thiazol-2-yl-amine,
1-benzyl-3-[4-methyl-5-(3-nitro-phenyl)-thiazol-2-yl]-urea,
1-[5-(3-amino-phenyl)-4-methyl-thiazol-2-yl]-3-benzyl-urea,
rac 3-pyridin-3-yl-pentanedicarboxylic acid monoethyl ester
ethyl [[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetate,
[[2-[(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-acetic acid,
tert-butyl (S)-N-benzyl-3-benzyloxycarbonylamino-succinamate,
tert-butyl (S)-3-amino-N-benzyl-succinamate,
tert-butyl (S)-3-benzyloxycarbonylamino-N-(3-methoxy-phenyl)-succinamate,
tert-butyl (S)-3-amino-N-(3-methoxy-phenyl)-succinamate,
tert-butyl (S)-2-(2-benzyloxycarbonylamino-3-tert-butoxycarbonyl-propionylamino)-benzoate,
tert-butyl (S)-2-(2-amino-3-tert-butoxycarbonyl-propionylamino)-benzoate,
ethyl 3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-benzoate,
3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-benzoic acid,
tert-butyl rac-3-tert-butoxycarbonylmethyl-2-oxo-piperidine-1-carboxylate,
tert-butyl rac-3-benzylcarbamoyl-6-tert-butoxycarbonylamino-hexanoate,
ethyl rac-6-amino-3-benzylcarbamoyl-hexanoate hydrochloride,
ethyl 2-phenoxycarbonylamino-thiazole-4-carboxylate,
ethyl 2-(3-pyridin-2-ylmethyl-ureido)-thiazole-4-carboxylate,
2-(3-pyridin-2-ylmethyl-ureido)-thiazole-4-carboxyhc acid,
ethyl 4-[2-(3-benzyl-ureido)-thiazol-4-yl]-butyrate,
4-[2-(3-benzyl-ureido)-thiazol-4-yl]-butyric acid,
diethyl rac-2-(3-bromo-2-oxo-propyl)-succinate,
diethyl rac-2-(3-azido-2-oxo-propyl)-succinate,
diethyl rac-2-(3-amino-2-oxo-propyl)-succinate,
tert-butyl (S)-3-benzyloxycarbonylamino-N-pyridin-2-ylmethyl-succinamate,
tert-butyl (S)-3-amino-N-pyridin-2-ylmethyl-succinamate,
tert-butyl (S)-3-benzyloxycarbonylamino-N-pyridin-3-ylmethyl-succinamate,
tert-butyl (S)-3-amino-N-pyridin-3-ylmethyl-succinamate,
tert-butyl (S)-3-(2-benzyloxycarbonylamino-acetylamino)-N-pyridin-2-ylmethyl-succinamate,
tert-butyl (S)-3-(2-amino-acetylamino)-N-pyridin-2-ylmethyl-succinamate,
ethyl 2-(imidazolidin-2-ylideneamino)-thiazole-4-carboxylate hydrobromide,
2-(imidazolidin-2-ylideneamino)-thiazole-4-carboxylic acid,
ethyl rac-3-(2-benzyloxycarbonylamino-acetylamino)-3-pyridin-3-yl-propionate,
ethyl 3-(2-amino-acetylamino)-3-pyridin-3-yl-propionate hydrochloride,
ethyl 4-methyl-2-(tetrahydro-pyrimidin-2-ylidenamino)-thiazole-5-carboxylate hydrochloride and
4-methyl-2-(tetrahydro-pyrimidin-2-ylideneamino)-thiazole-5-carboxylic acid.
The compounds of formula I described above for use as therapeutically active substances are a further object of the invention.
Also an object of the invention are compounds described above for the production of medicaments for the prophylaxis and therapy of illnesses which are caused by a malfunction of the binding of adhesive proteins to vitronectin receptors.
Likewise an object of the invention are pharmaceutical compositions containing a compound of formula I described above and a therapeutically inert carrier. The invention likewise relates to a pharmaceutical composition as previously described, which additonally contains one or more compounds of general formula I or additionally one or more compounds selected from the group comprising anticoagulants, fibrinolytics as well as medicaments for the prophylaxis and therapy of illnesses which are caused by a malfunction of the binding of adhesive proteins to vitronectin receptors.
An object of the invention is also the use of the compounds described above for the production of medicaments for the treatment or prophylaxis of illnesses which are caused by a malfinction of the binding of adhesive proteins to vitronectin receptors.
Also an object of the invention is the use of one of the compounds described above for the production of medicaments e.g. for the treatment or prophylaxis of neoplasms, tumor metastasing, tumor growth, osteoporosis, Paget""s disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure as well as infections caused by viruses, bacteria or fungi.
A further object of the invention comprises compounds which are manufacturable according to one of the described processes.
Likewise an object of the invention are methods for the treatment and prophylaxis of illnesses which are caused by a malfunction of the binding of adhesive proteins to vitronectin receptors and which are comprise by the administration of an effective amount of a compound of formula I.
A further object of the invention is a method for the treatment and phophylaxis of neoplasms, tumor metastasing, tumor growth, osteoporosis, Paget""s disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure as well as infections caused by viruses, bacteria or fungi, whereby an effective amount of one of the compounds described above is administered.
Likewise an object of the invention are compounds described above for the treatment and prophylaxis of neoplasms, tumor metastasing, tumor growth, osteoporosis, Paget""s disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure as well as infection caused by viruses, bacteria or fungi.
The conversion of a compound of formula I into a pharmaceutical usable salt can be carried out by treatment of such a compound with an inorganic acid, for example a hydrohalic acid, such as, for example, hydrochloric acid or hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc., or with an organic acid, such as, for example, acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulphonic acid or p-toluenesulphonic acid.
The corresponding carboxylate salts can also be prepared from the compounds of formula I by treatment with physiologically compatible bases.
The conversion of a compound of formula I into a pharmaceutically usable ester can be accomplished by treatment of such a compound in the usual or as described in the Examples.
As mentioned previously, the compounds of formula I and their pharmaceutically usable salts and esters inhibit especially the binding of various adhesive proteins such as fibrinogen, vitronectin, von Willebrand factor, fibronectin, thrombospondin and osteopontin to the vitronectin receptors (such as e.g. xcex1vxcex23, xcex1vxcex25, xcex1vxcex26, xcex1vxcex28 etc.) on the surface of different types of cell. The compounds therefore influence cell-cell and cell-matrix interactions. Since the vitronectin receptors play a rxc3x4le, inter alia, in the spread of tumor cell, in vascular regeneration, in the degradation of bone tissue, in the migration of smooth muscle cells in vascular walls and in the invasion of virus particles into target cells, the said compounds can be used as vitronectin receptor antagonists in the control or prevention of neoplasms, tumor metestasing, osteoporosis, Paget""s disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, kidney failure as well as infections caused by viruses, bacteria or by fungi. Since the binding of the adhesive proteins to the fibrinogen receptor (xcex1IIbxcex23) on the surface of blood platelets is practically not inhibited) undesired side effects, such as e.g. bleeding, can be suppressed with the therapeutic application of the said compounds.
The inhibition of the binding of adhesive proteins such as e.g. fibrinogen to vitronectin receptors (such as e.g. xcex1vxcex23, xcex1vxcex25, xcex1vxcex26, xcex1vxcex28, etc.) by compounds of the present invention can be determined as described by L. Alig et al. [J. Med. Chem., 35: 4393-4407 (1992)].
In detail thereto, the wells of microtitre plates (Nunc-Immunoplate MaxiSorp) were coated overnight at 4xc2x0 C. with the vitronectin receptor xcex1vxcex23 (from human placenta, 100 xcexcl/well) in a buffer system with 150 mmol/l NaCl, 1 mmol/CaCl2, 1 mmol/l MgCl2, 0.0005% Triton X-100 and 20 mmol/l Tris HCl, pH 7.4. The non-specific binding sites were blocked by incubation with 3.5% bovine serum albumin (BSA from Fluka) at 20xc2x0 C. for at least 1 h. Before the beginning of the test the plates were washed in each case once with 150 mmol/l NaCl, 1 mmol/l CaCl2, 1 mmol/l MgCl2 and 20 mmol/l Tris HCl, pH 7.4 (buffer A). The thus-coated plates can be stored for at least 2 months in the presence of 0.05% NaN3 (in buffer A) at 4xc2x0 C. in a humidity chamber without loss of binding activity. Fibrinogen (IMCO, free from fibronectin) was diluted to 1.5 xcexcg/ml in buffer A in the presence of 1% BSA. The wells coated with the receptor were incubated with fibrinogen (100 xcexcl/well) overnight at room temperature in the absence of or in the presence of increasing concentrations of RGDS (as the reference substance) or the compounds to be measured. Non-bound fibrinogen was removed by three-fold washing with buffer A, bound fibrinogen was detected by an ELISA procedure. Antibodies of rabbits directed against human fibrinogen (Dakopatts, Denmark), diluted in buffer A in the presence of 0.1% BSA, were added at room temperature for 1 h., followed by incubation with biotinylated antibodies directed against rabbit immunoglobulin (Amersham) for 30 min. Non-bound antibodies were removed by three-fold washing with buffer A. Thereafter, the pre-formed streptavidin-biotinylated peroxidase complex (Amersham) was added for 30 min. three-fold washing with buffer A was again carried out. After addition of the peroxidase substrate ABTS (2,2xe2x80x2-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid), Boehringer Mannheim) the enzyme activity was measured with a multichannel photometer (UVmax, Molecular Devices). The difference between total binding activity (in the absence of a test substance) and non-specific binding activity (in the presence of 100 xcexcM RGDS) is taken as the specific binding activity. The concentration of a test substance which is required to inhibit the specific binding activity by 50% was defined as the IC50.
The isolation of the receptor xcex1vxcex23 used in the test can be carried out as follows: Human placenta is stored at xe2x88x9280xc2x0 C. immediately after its excision. In order to extract the receptor, each placenta is superficially thawed and cut into narrow strips with a scalpel. The pieces are washed twice with a buffer of 150 mmol/l NaCl, 1 mmol/l CaCl2, 1 mmol/l MgCl2 and 20 mmol/l Tris HCl (pH 7.4). The proteins are extracted at room temperature for one hour with a buffer solution from 1% Triton X-100, 150 mmol/l NaCl, 1 mmol/l CaCl2, 1 mmol/l MgCl2, 20 mmol/l Tris HCl, 0.02% NaN3, 0.5 mmol/l phenylmethanesulphonyl fluoride, 1 mmol/l leupeptin and 2 mmol/l N-ethylmaleimide (pH 7.4) and filtered through sterile gauze. The filtrate is centrifuged at 30000 g for 30 min. at 4xc2x0 C. The glycoproteins are firstly separated with the aid of a concanavalin A-Sepharose 4B column. The proteins bound to the column are eluted and then added to a Aeg-RGDS column. After repeated washing the bound vitronectin receptor is eluted by 3 mmol/l RGDS in a buffer of 0.1% Triton X-100, 150 mmol/l NaCl, 20 mmol/l Tris HCl, 1 mmol/l CaCl2, 1 mmol/l MgCl2, 0.05% NaN3 (pH 7.0).
Table 1 shows examples of compounds according to formula 1, wherein these compounds have IC50 values below 1 xcexcM. These results have been obtained by using the foregoing test.
rac 3-[2-[[(2-[(3-Benzyl-ureido)-thiazol-4-ylcarbonyl]-amino]-acetylamino]-3-phenyl-propionic acid
rac 4-[3-(2-Guanidino-4-methyl-thiazol-5-yl)-phenylcarbamoyl]-3-phenyl-butyric acid
rac 3-[2-[(2-Guanidinomethyl-thiazol-4-ylcarbonyl)-amino]-acetylamino]-3-phenyl-propionic acid
rac 3-[3-[(2-Guanidino-4-methyl-thiazol-5-carbonyl)-amino]-benzoylamino]-3-phenyl-propionic acid-hydrochloride
rac 3-[3-[(4-tert-Butyl-2-guanidino-thiazol-5-ylcarbonyl)-amino]-benzoylamino]-3-pyridin-3-yl-propionic acid
[2-Guanidino-thiazol-4-carbonyl]-Gly-Asp-Val-OH hydrochloride
(S)-N-Benzyl-3-(2-((2-(3-benzyl-ureido)-thiazole-4-carbonyl)-amino)-acetylamino)-succinamate trifluoroacetate
Preferred compounds as described above have an IC50 which is below 100 xcexcM; especially preferred compounds have a value below 10 xcexcM, particularly preferred compounds have a value below 1 xcexcM.
The compounds of formula I and their pharmaceutically usable salts and esters can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
The compounds of formula I and their pharmaceutical usable salts and esters can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragxc3xa9es and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragxc3xa9es and hard gelatine capsules.
Suitable adjuvants for soft gelatine capsules, are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
Suitable for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
Moreover, the pharmaceutical preparations, can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
In accordance with the invention the compounds of formula I and their pharmaceutically usable salts and esters can be used as vitronectin receptor antagonists especially for the treatment or prophylaxis of neoplasms, tumor metastasing, tumor growth, osteoporosis, Paget""s disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure as well as infections caused by viruses, bacteria or fungi. The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given above can be exceeded when this is shown to be indicated.